1. Field of the Invention
This invention generally relates to antagonists of melanin-concentrating hormone receptors, and to compositions and methods related thereto.
2. Description of the Related Art
Melanin-concentrating hormone (MCH) is a neuropeptide that exerts a powerful effect on food intake and body weight regulation (Broberger & Hokfelt, PHYSIOL. BEHAV. 2001 November–December; 74(4–5): 669–82). As a result, this neuropeptide, as well as antagonists to its various receptors, has been investigated for use in therapies relating to eating and body weight regulating disorders.
More specifically, MCH is a cyclic neuropeptide that is over expressed in obese mice. Experiments where MCH was directly injected into lateral ventricles of the brains of rats resulted in increased consumption of food, indicating that MCH has a role in the regulation of body weight (Qu, et al., NATURE 1996 Mar. 21; 380 (6571):243–7). The orexigenic (appetite-stimulating) activity is believed to result from MCH's binding to a melanin-concentrating hormone receptor (MCH-1R) determined to be a 353 amino acid human orphan G-Protein-Coupled Receptor (GPCR) SLC-1 (Chambers et al., NATURE 1999 Jul. 15; 400(6741): 261–5; Saito et al., NATURE 1999 Jul. 15; 4000(6741): 265–9). Mice deficient in MCH-1R have normal body weights, yet are lean and have reduced fat mass; thus, less susceptible to diet-induced obesity (Marsh et al., PROC. NATL. ACAD. SCI. 2002 Mar. 5; 99 (5): 3240–5). A second MCH receptor (MCH-2R) has also been identified (Sailer et al., PROC. NATL. ACAD. SCI. 2001 Jun. 19; 98(13): 7564–9; An et al. PROC. NATL. ACAD. SCI. 2001 Jun. 19; 98(13): 7576–81).
In view of its biological importance, a number of researchers have reported proteins or small molecule antagonists to MCH receptors. For example, Merck Research Laboratories has reported protein agonists consisting of the cyclic core of human MCH that activates both MCH-1R and MCH-2R, and an agonist with selectivity for MCH-1R (Bednarek et al., J BIOL CHEM 2002 Apr. 19; 277(16): 13821–6). Takeda Chemical Industries (Takeda) has disclosed the use of (−)-N-[6-(dimethylamino)-methyl]-5,6,7,8-tetrahydro-2-naphthalenyl]-4′-fluoro-[1,1′-biphenyl]-4-carboxamide and derivatives thereof as selective MCH-1R inhibitors (Kakekawa et al., EUR J PHAMOCOL 2002 Mar. 8; 438(3); 129–35; WO 01/21577). Additional Takeda patent publications directed to MCH antagonists include JP 2001226269; WO 01/21169; WO 01/82925; and WO 01/87834. Synaptic Pharmaceutical Corporation has similarly disclosed MCH receptor antagonists (WO 02/06245), as has Neurogen Corporation (WO 02/04433; U.S. 20020052383 A1).
Accoringly, there remains a need in the art for novel MCH receptor antagonists, including antagonists of MCH-1R and/or MCH-2R, and for compositions and methods related thereto. The present invention fulfils these needs and provides further related advantages.